CN102584846A - Curcumenol derivatives resisting influenza A(H1N1) virus - Google Patents
Curcumenol derivatives resisting influenza A(H1N1) virus Download PDFInfo
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Abstract
The invention belongs to the technical field of medical technology, and relates to novel compounds, which are shown in a general formula (I) and have the activity of resisting influenza A(H1N1) virus, wherein R1 and R2 are defined as in the specification. The invention also relates to application and a preparation method of the compounds, and clinically acceptable medicines for treating infectious diseases of influenza A(H1N1) virus, which are prepared by combining the compounds with pharmaceutically acceptable carriers. The structure of formula (I) is shown in the specification.
Description
Technical field
The present invention relates to medical technical field, definite saying so relates to a kind of Curcumenol verivate of anti-influenza A H 1 N 1 virus.
Background technology
Influenza (influenza) is that the healthy a kind of infectivity of the serious harm people, animal fowl that caused by influenza virus is strong, and the acute viral respiratory infectious disease that velocity of propagation is fast is a kind of typical zoonosis.Medical circle is generally acknowledged: the harm of influenza is not second to AIDS and war.Caused complication of influenza and death are very serious.According to the bulletin of World Health Organization (WHO) issue, global annual influenza case is 600,000,000-1,200,000,000 examples, dead 500,000-1,000,000 people, and severe influenza case 3,000,000-5,000,000 example wherein, the case fatality rate of severe influenza is 8%-10%.Influenza causes tremendous economic loss and burden on society also can for a country except that causing a large amount of population morbidities and death.According to recent statistics, the financial loss that only causes because of influenza in U.S. every year is up to 71,000,000,000-1,670 hundred million dollars.Therefore we can say that influenza is one of disease of serious threat human health, the prevention of influenza is very urgent.
Can influenza virus be divided into first, second, the third three types according to influenza virus nucleoprotein (NP) and stromatin (MP) antigenic specificity.Wherein influenza A causes popularly on a large scale easily, and what pay close attention to both at home and abroad mainly is influenza A virus.Influenza A virus, different according to surface antigen HA and NA can be divided into some hypotypes, found at present 16 kinds of HA (H1-H16), 9 kinds of NA (N1-N9) antigen (J Virol, 2005,79:2814-2822).The Influenza A H1N1 that have swept the globe in 2009 by in January, 2010, causes 208 countries and regions, the whole world to report 250,000 cases, and wherein 12799 people are dead.The H1N1 influenza virus is with artificial main contagium; The spittle that mainly cough through the infected and sneezing etc. produces or aerosol are through respiratory infectious; But also through port, nasal cavity, eyes etc. locate the direct or indirect contact transmission of mucous membrane (Annu Rev Immunol, 2001,19:683-765).
The research of antiviral chemical medicine originates in the 1950's; Remain the main means of treatment virus disease up to now, but effect is not remarkable, special so far, effective antiviral compound still seldom; And antiviral spectrum is narrower, and very easily produces resistance.Mainly contain two types of anti-influenza virus medicaments at present: one type is the influenza virus neuraminidase inhibitor class, comprises Tamiflu and zanamivir; Another kind of is adamantane, comprises amantadine and Rimantadine.For in the Influenza A H1N1 medicine clinical very effective be exactly Tamiflu be the Ro 64-0796/002 capsule, it can stop virus in infected human body, to be bred, and H1N1virus has resistance to Derivatives of Adamantane.Therefore, the medicine of treatment Influenza A H1N1 is extremely limited, and because existing medicine widespread use clinically can make that virus morphs, thereby produce resistance in various degree.And some Chinese medicines, like (practical medical magazine, 2007 such as Japanese Honeysuckle, the capsule of weeping forsythia, Herba Andrographis, Root of Indigowoad, the roots of large-flowered skullcap; 14:3218-3219), have antivirus action preferably, but the complicacy of effective component or indeterminate property; Bring the potential safety issue to clinical application, traditional Chinese medicine such as SHUANGHUANLIAN, Herba Houttuyniae particularly, visible often report (the pharmacoepidemiology magazine that occurs spinoff clinically; 2005,14:148-151; The pharmacoepidemiology magazine, 2007,16:25-26).Therefore, the medicine of seeking the anti-H1N1 influenza virus of efficient, low toxicity has become the problem that the world of medicine pays close attention to.
Chinese medicine curcuma zedoary and volatile oil preparation thereof are widely used in clinical as antiviral.2010 editions pharmacopeia regulation Curcumenols are the index components of clinical antiviral zedoary turmeric oil quality control.Pharmaceutical research show Curcumenol have antiviral, antitumor, protect the liver, many-sided effect such as antiearly pregnancy.Curcumenol has the pharmacologically active consistent with zedoary turmeric oil, and therefore, Curcumenol is one of main pharmacodynamics composition of zedoary turmeric oil.But because it is water-soluble very poor, only be soluble in the little polar organic solvents such as ethanol, acetone, chloroform, fail to be developed as clinical application for a long time always.In view of chemistry in its structure can change the limitation in site, the report that adopts the organic chemistry method that it is carried out structural modification up to now is fewer.This seminar has carried out chemical structure to Curcumenol and has modified research, and has found to have the reactive derivative of good resistance H1N1virus.
Summary of the invention
Primary and foremost purpose of the present invention is the Curcumenol verivate that provides new.
Another object of the present invention is to provide the preparation method of said Curcumenol verivate.
A purpose more of the present invention is to provide the application of said Curcumenol verivate aspect treatment H 1 N 1 influenza A virus infection property disease.
Compound of the present invention has the structure of formula I:
Wherein, R
1Represent fragrant oxygen base, acyloxy, C
1-6Ring-shaped fat amino (comprise and contain O, the equiatomic heterocycle of S), benzyl amino; R
2Represent OH or OAc.
The chemical name and the chemical structural formula of new Curcumenol verivate of the present invention are preferably following:
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-to aldehyde radical phenoxy Guajol (
1)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8-hydroxyl-14-Guajol acetic ester (
2)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8-hydroxyl-14-Guajol succinate (
3)
(1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9,10-alkene-8,14-pockwood ethyl glycol acetate (
4)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-Pyrrolidine base Guajol (
5)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-piperidyl Guajol (
6)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-N-N-METHYL PIPERAZINE base Guajol (
7)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-morpholinyl Guajol (
8)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-thio-morpholinyl Guajol (
9)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-to the amino Guajol of methoxybenzyl (
10)
The invention provides the preparation method of above-claimed cpd:
Curcumenol exists
mUnder the effect of-CPBA, obtained 14 double bond epoxidations after, under alkaline condition,, formed crucial midbody (1S through open loop dehydration; 4S, 5S, 7S, 8R)-5,8-epoxy-9; 10-alkene-8,14-pockwood glycol on the basis of mesosome, directly synthesizes above-claimed cpd hereinto
3With
4And the intermediate ethanol hydroxyl is converted into the higher halohydrocarbon of reactivity ratio, designed and synthesized above-claimed cpd
1-
2With
5-10
Said Curcumenol verivate can be used as H 1 N 1 influenza A virus infection treatment of diseases medicine.
Said anti-H1N1 influenza virus medicine contains the above-mentioned Curcumenol verivate and the pharmaceutically acceptable carrier of treating significant quantity.
Curcumenol verivate of the present invention can be processed various conventional formulations and formulation with the various auxiliary materials of available on the pharmacy meaning; Adopt oral, parenteral (for example; Intramuscular, intraperitoneal, intravenously, intracisternal injection or infusion, subcutaneous injection or implantation; Or through sucking sprays, or intranasal, vagina, rectum, hypogloeeis or topical approach) mode of administration, for example; Can be tablet, tincture, moisture or oil suspension, dispersible powder, granule, emulsion, syrup, injection, hard capsule or soft capsule etc., be used to treat anti-influenza A H 1 N 1 virus and catch.
The relative prior art of the present invention has following advantage and effect:
(1) compound of new anti-influenza A H 1 N 1 virus is provided, wherein compound
4With
8The anti-influenza A H 1 N 1 virus activity is stronger than Tamiflu; (2) preparation technology of above-claimed cpd of the present invention is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial prodn, has good research and development prospect.
Embodiment
The present invention can explain through following embodiment.
Embodiment 1: The compounds of this invention (
1) preparation
The preparation of midbody:
Will
m(17.2g 1mol) is dissolved in the methylene dichloride (100ml)-CPBA, and (11.8g in methylene dichloride 0.05mol) (100ml) solution, keeps 0 ℃ to stir 2 hours to join Curcumenol under 0 ℃.After reaction finished, reaction solution was with NaOH (2mol/l) solution extraction 3 times, the merging organic phase, and water is extracted to neutrality again, anhydrous sodium sulfate drying.With the solution concentration evaporate to dryness, get bullion through silica gel chromatography (hexanaphthene: ETHYLE ACETATE=50: 1～10: 1) obtain white waxy solid 10,14-epoxy Curcumenol 11.95g, yield 95%.
With 10,14-epoxy Curcumenol (10.08g 0.04mol) is dissolved in the acetonitrile in (600ml), add under the room temperature three water lithium perchlorates (6.4g, 0.04mol), diethylamine (20ml).The gained mixture heating up refluxes and spends the night.Reaction solution concentrates evaporate to dryness, extracts 3 times with isopyknic ETHYLE ACETATE and water, merges organic phase, anhydrous sodium sulfate drying.With the solution concentration evaporate to dryness, bullion through silica gel chromatography (hexanaphthene: ETHYLE ACETATE=10: 1～4: 1) white, needle-shaped crystals (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8,14-pockwood glycol 3.04g, yield 30%.The spectral data of compound is following: MS (ESI)
M/z: 275.2 [M+Na]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 1.98 (1H, dd,
J=9.2,15.3Hz, H-1), 1.89 (1H, m, H-2a), 1.52 (1H, m, H-2b), 1.89 (1H, m, H-3a), 1.56 (1H, m, H-3b), 1.80 (1H, m, H-4), 2.19 (1H, dd,
J=11,12.6Hz, H-6a), 1.23 (1H, dd,
J=7.3,12.6Hz, H-6B), 1.65 (1H, dd,
J=3.2,10.6Hz, H-7), 5.8 (1H, s, H-9), 1.45 (1H, m, H-11), 0.85 (3H, d,
J=6.4Hz, H-12), 0.98 (3H, d,
J=6.4Hz, H-13), 4.06 (2H, brs, H-14), 1.00 (3H, d,
J=5.3Hz, H-15);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 49.8 (C-1), 27.8 (C-2), 31.4 (C-3), 40.4 (C-4), 87.4 (C-5), 36.6 (C-6), 59.6 (C-7), 103.7 (C-8), 123.8 (C-9), 144.1 (C-10), 31.0 (C-11), 22.8 (C-12), 21.6 (C-13), 64.6 (C-14), 11.9 (C-15).
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9,10-alkene-8, (2.52g, 0.01mol), (5.24g 0.02mol) joins CCl to triphenylphosphine to 14-pockwood glycol successively
4/ CH
2Cl
2(1: 1,400ml).The gained mixture heating up refluxed 3 hours.Reaction solution concentrates evaporate to dryness, bullion through silica gel chromatography (hexanaphthene: ETHYLE ACETATE=50: 1～10: 1) white oily compound (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-chloro Guajol 2.56g, yield 95%.
Target compound (
1) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5; 8-epoxy-9,10-alkene-14-chloro Guajol (27mg 0.1mmol) is dissolved in the acetone (4ml), and the adding PARA HYDROXY BENZALDEHYDE (14.6mg, 0.12mmol); Anhydrous potassium carbonate (20.7mg, 0.15mmol), potassiumiodide (5mg, 0.03mmol).The gained mixture heating up refluxed 3 hours.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=2.5: 1, eluent ethyl acetate) the colorless oil compound (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-to aldehyde radical phenoxy Guajol (
1) 28.8mg, yield 81%.The spectral data of compound is following: MS (ESI)
M/z: 379.0 [M+Na]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.08 (1H, t, 8.3Hz, H-1), 1.91 (1H, m, H-2a), 1.60 (1H, m, H-2b), 1.91 (1H, m, H-3a), 1.61 (1H, m, H-3b), 1.83 (1H, m, H-4), 2.20 (1H, dd,
J=10.9,12.6Hz, H-6a), 1.20 (1H, dd,
J=7.3,12.7Hz, H-6b), 1.65 (1H, dd,
J=3.1,10.4Hz, H-7), 5.93 (1H, s, H-9), 1.41 (1H, m, H-11), 0.83 (3H, d,
J=6.5Hz, H-12), 0.96 (3H, d,
J=6.5Hz, H-13), 4.52 (2H, brs, H-14), 1.00 (3H, d,
J=6.4Hz, H-15), 6.99 (2H, d,
J=8.7Hz, H-2 ', H-6 '), 7.80 (2H, d,
J=8.7Hz, H-3 ', H-5 '), 9.86 (1H, s ,-CHO);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 49.7 (C-1), 27.6 (C-2), 31.3 (C-3), 40.4 (C-4), 87.3 (C-5), 36.6 (C-6), 59.9 (C-7), 103.5 (C-8), 127.3 (C-9), 139.3 (C-10), 31.0 (C-11), 22.8 (C-12), 21.5 (C-13), 69.9 (C-14), 11.9 (C-15), 163.8 (C-1 '), 115.3 (C-2 '; C-6 '), 132.1 (C-3 ', C-5 '), 130.3 (C-4 '), 191.0 (CHO).
Embodiment 2: The compounds of this invention (
2) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
2) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-chloro Guajol (27mg 0.1mmol) is dissolved among the DMF (2ml), and the adding sodium-acetate (12.3mg, 0.15mmol).70 ℃ of reactions of gained mixture 3.5 hours.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=3: 1, eluent ethyl acetate) the colorless oil compound (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8-hydroxyl-14-Guajol acetic ester (
2) 21.2mg, yield 72%.The spectral data of compound is following: MS (ESI)
M/z: 317.0 [M+Na]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 1.96 (1H, dd,
J=8.8,16.4Hz, H-1), 1.87 (1H, m, H-2a), 1.56 (1H, m, H-2b), 1.87 (1H, m, H-3a), 1.56 (1H, m, H-3b), 1.80 (1H, m, H-4), 2.19 (1H, dd,
J=10.7,12.6Hz, H-6a), 1.22 (1H, dd,
J=7.4,12.6Hz, H-6b), 1.62 (1H, dd,
J=3.3,10.6Hz, H-7), 5.81 (1H, s, H-9), 1.45 (1H, m, H-11), 0.86 (3H, d,
J=6.5Hz, H-12), 0.97 (3H, d,
J=6.5Hz, H-13), 4.49 (2H, dd,
J=13.5,24.9Hz, H-14), 1.00 (3H, d,
J=4.8Hz, H-15), 2.07 (3H, s ,-CH
3);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 49.9 (C-1), 27.6 (C-2), 31.3 (C-3), 40.4 (C-4), 87.3 (C-5), 36.6 (C-6), 59.9 (C-7), 103.4 (C-8), 126.5 (C-9), 139.2 (C-10), 30.9 (C-11), 22.8 (C-12), 21.6 (C-13), 65.6 (C-14), 11.9 (C-15), 170.9 (C=O), 21.1 (CH
3).
Embodiment 3: The compounds of this invention (
3) preparation
The preparation of midbody: with
Embodiment 1Middle midbody (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8, the preparation method of 14-pockwood glycol.
Target compound (
3) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9,10-alkene-8,14-pockwood glycol (25.2mg 0.1mmol) is dissolved in the anhydrous pyridine (4ml), and the adding Succinic anhydried (15mg, 0.15mmol), DMAP (2.5mg, 0.02mmol).70 ℃ of reactions of gained mixture 2 hours.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=2: 1, eluent ethyl acetate) the colorless oil compound (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8-hydroxyl-14-Guajol succinate (
3) 24.6mg, yield 71%.The spectral data of compound is following: MS (ESI)
M/z: 361.2 [M+Na]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 1.95 (1H, dd,
J=8.8,16.3Hz, H-1), 1.86 (1H, m, H-2a), 1.52 (1H, m, H-2b), 1.86 (1H, m, H-3a), 1.52 (1H, m, H-3b), 1.80 (1H, m, H-4), 2.18 (1H, dd,
J=11.2,12.3Hz, H-6a), 1.21 (1H, dd,
J=7.2,12.3Hz, H-6b), 1.65 (1H, dd,
J=3.1,10.5Hz, H-7), 5.82 (1H, s, H-9), 1.43 (1H, m, H-11), 0.84 (3H, d,
J=6.5Hz, H-12), 0.96 (3H, d,
J=6.5Hz, H-13), 4.52 (2H, dd,
J=13.4,26.0Hz, H-14), 0.98 (3H, d,
J=4.6Hz, H-15), 2.64 (4H, brs ,-CH
2-);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 50.0 (C-1), 27.6 (C-2), 31.2 (C-3), 40.4 (C-4), 87.7 (C-5), 36.5 (C-6), 59.3 (C-7), 103.7 (C-8), 127.0 (C-9), 138.8 (C-10), 30.9 (C-11), 22.8 (C-12), 21.5 (C-13), 65.9 (C-14), 11.8 (C-15), 177.3 (C=O), 172.0 (C=O), 29.1 (CH
2-).
Embodiment 4: The compounds of this invention (
4) preparation
The preparation of midbody: with
Embodiment 1Middle midbody (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8, the preparation method of 14-pockwood glycol.
Target compound (
4) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9,10-alkene-8,14-pockwood glycol (25.2mg 0.1mmol) is dissolved in the anhydrous pyridine (4ml), adds diacetyl oxide (30 μ l), and DMAP (2.5mg, 0.02mmol).70 ℃ of reactions of gained mixture 2 hours.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=5: 1, eluent ethyl acetate) the colorless oil compound (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8,14-pockwood ethyl glycol acetate (
4) 28.8mg, yield 86%.The spectral data of compound is following:
1H-NMR (300 MHz, CDCl
3)
δ(ppm): 1.95 (1H, dd,
J=8.5,17.2Hz, H-1), 1.85 (1H, m, H-2a), 1.60 (1H, m, H-2b), 1.85 (1H, m, H-3a), 1.61 (1H, m, H-3b), 1.82 (1H, m, H-4), 2.15 (1H, dd,
J=10.7,12.6Hz, H-6a), 1.18 (1H, dd,
J=7.4,12.6Hz, H-6b), 1.62 (1H, dd,
J=3.3,10.6Hz, H-7), 5.85 (1H, s, H-9), 1.48 (1H, m, H-11), 0.86 (3H, d,
J=6.6Hz, H-12), 0.90 (3H, d,
J=6.6Hz, H-13), 4.49 (2H, dd,
J=13.2,21.3Hz, H-14), 0.98 (3H, d,
J=6.1Hz, H-15), 2.04 (3H, s ,-CH
3), 2.06 (3H, s ,-CH
3);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 49.8 (C-1), 27.7 (C-2), 31.2 (C-3), 40.4 (C-4), 88.9 (C-5), 35.2 (C-6), 57.5 (C-7), 105.5 (C-8), 126.1 (C-9), 136.3 (C-10), 30.5 (C-11), 22.7 (C-12), 21.4 (C-13), 65.9 (C-14), 11.8 (C-15), 170.9 (C=O), 168.6 (C=O), 21.2 (CH
3), 22.3 (CH
3).
Embodiment 5: The compounds of this invention (
5) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
5) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9, (27mg 0.1mmol) is dissolved among the DMF (2ml) 10-alkene-14-chloro Guajol, adds Pyrrolidine (50 μ l).70 ℃ of reactions of gained mixture are spent the night.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=1: 1, eluent ethyl acetate) white waxy solid (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-Pyrrolidine base Guajol (
5) 25.9mg, yield 85%.The spectral data of compound is following: MS (ESI)
M/z: 306.1 [M+H]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.10 (1H, t,
J=8.5Hz, H-1), 1.86 (1H, m, H-2a), 1.50 (1H, m, H-2b), 1.86 (1H, m, H-3a), 1.54 (1H, m, H-3b), 1.79 (1H, m, H-4), 2.18 (1H, dd,
J=10.7,12.5Hz, H-6a), 1.20 (1H, dd,
J=7.3,12.5Hz, H-6b), 1.62 (1H, dd,
J=3.2,10.6Hz, H-7), 5.71 (1H, s, H-9), 1.44 (1H, m, H-11), 0.86 (3H, d,
J=6.4Hz, H-12), 0.97 (3H, s, H-13), 3.27 (1H,
J=13.2Hz, H-14a), 2.65 (1H,
J=13.2Hz, H-14b), 1.00 (3H, s, H-15), 2.44 (4H, brs, N-1), 1.76 (4H, brs, N-2);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 50.6 (C-1), 27.8 (C-2), 31.2 (C-3), 40.5 (C-4), 87.0 (C-5), 36.8 (C-6), 59.8 (C-7), 103.5 (C-8), 125.6 (C-9), 143.3 (C-10), 31.2 (C-11), 23.0 (C-12), 21.6 (C-13), 60.7 (C-14), 12.0 (C-15), 54.7 (N-1), 23.7 (N-2).
Embodiment 6: The compounds of this invention (
6) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
6) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9, (27mg 0.1mmol) is dissolved among the DMF (2ml) 10-alkene-14-chloro Guajol, adds piperidines (50 μ l).70 ℃ of reactions of gained mixture are spent the night.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=1: 1, eluent ethyl acetate) white waxy solid (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-piperidyl Guajol (
6) 12.7mg, yield 63%.The spectral data of compound is following: MS (ESI)
M/z: 320.2 [M+H]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.06 (1H, t,
J=8.2Hz, H-1), 1.87 (1H, m, H-2a), 1.51 (1H, m, H-2b), 1.87 (1H, m, H-3a), 1.54 (1H, m, H-3b), 1.80 (1H, m, H-4), 2.18 (1H, dd,
J=10.7,12.6Hz, H-6a), 1.20 (1H, dd,
J=7.3,12.6Hz, H-6b), 1.62 (1H, m, H-7), 5.71 (1H, s, H-9), 1.45 (1H, m, H-11), 0.86 (3H, d,
J=6.5Hz, H-12), 0.97 (3H, s, H-13), 2.98 (1H,
J=13.5Hz, H-14a), 2.64 (1H,
J=13.5Hz, H-14b), 1.00 (3H, s, H-15), 2.30 (4H, brs, N-1), 1.54 (4H, m, N-2), 1.41 (2H, m, N-3);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 50.9 (C-1), 27.7 (C-2), 31.3 (C-3), 40.4 (C-4), 87.0 (C-5), 36.8 (C-6), 59.9 (C-7), 103.5 (C-8), 126.0 (C-9), 142.5 (C-10), 31.2 (C-11), 22.9 (C-12), 21.6 (C-13), 63.4 (C-14), 12.0 (C-15), 55.0 (N-1), 26.0 (N-2), 24.5 (N-3).
Embodiment 7: The compounds of this invention (
7) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
7) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9, (27mg 0.1mmol) is dissolved among the DMF (2ml) 10-alkene-14-chloro Guajol, adds N methyl piperazine (50 μ l).70 ℃ of reactions of gained mixture are spent the night.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=1: 1, eluent ethyl acetate) white waxy solid (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-N-N-METHYL PIPERAZINE base Guajol (
7) 23.7mg, yield 71%.The spectral data of compound is following: MS (ESI)
M/z: 335.1 [M+H]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.03 (1H, t,
J=8.9Hz, H-1), 1.86 (1H, m, H-2a), 1.47 (1H, m, H-2b), 1.86 (1H, m, H-3a), 1.50 (1H, m, H-3b), 1.80 (1H, m, H-4), 2.18 (1H, dd,
J=10.8,12.5Hz, H-6a), 1.16 (1H, dd,
J=7.3,12.5Hz, H-6b), 1.62 (1H, dd,
J=3.1,10.5Hz, H-7), 5.71 (1H, s, H-9), 1.40 (1H, m, H-11), 0.85 (3H, d,
J=6.5Hz, H-12), 0.97 (3H, s, H-13), 3.00 (1H,
J=13.5Hz, H-14a), 2.68 (1H,
J=13.5Hz, H-14b), 0.99 (3H, s, H-15), 2.42 (4H, brs, N-1), 2.42 (4H, brs, N-2), 2.26 (3H, s, N-3);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 50.9 (C-1), 27.6 (C-2), 31.4 (C-3), 40.5 (C-4), 86.9 (C-15), 36.9 (C-6), 59.8 (C-7), 103.4 (C-8), 126.7 (C-9), 141.8 (C-10), 31.2 (C-11), 23.0 (C-12), 21.6 (C-13), 62.5 (C-14), 12.1 (C-15), 55.3 (N-1), 55.3 (N-2), 46.2 (N-3).
Embodiment 8: The compounds of this invention (
8) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
8) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9, (27mg 0.1mmol) is dissolved among the DMF (2ml) 10-alkene-14-chloro Guajol, adds morpholine (50 μ l).70 ℃ of reactions of gained mixture are spent the night.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=1: 1, eluent ethyl acetate) white waxy solid (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-morpholinyl Guajol (
8) 28.6mg, yield 89%.The spectral data of compound is following: MS (ESI)
M/z: 322.2 [M+H]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.05 (1H, t,
J=8.7Hz, H-1), 1.89 (1H, m, H-2 a), 1.50 (1H, m, H-2b), 1.89 (1H, m, H-3a), 1.52 (1H, m, H-3b), 1.80 (1H, m, H-4), 2.18 (1H, dd,
J=10.7,12.6Hz, H-6a), 1.18 (1H, dd,
J=7.4,12.6Hz, H-6b), 1.62 (1H, dd,
J=3.2,10.6Hz, H-7), 5.73 (1H, s, H-9), 1.39 (1H, m, H-11), 0.86 (3H, d,
J=6.5Hz, H-12), 0.97 (3H, s, H-13), 3.00 (1H,
J=13.5Hz, H-14a), 2.68 (1H,
J=13.5Hz, H-14b), 0.99 (3H, s, H-15), 2.37 (4H, brs, N-1), 3.68 (4H, brs, N-2);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 50.9 (C-1), 27.7 (C-2), 31.4 (C-3), 40.5 (C-4), 87.0 (C-5), 36.9 (C-6), 59.9 (C-7), 103.5 (C-8), 126.8 (C-9), 141.4 (C-10), 31.2 (C-11), 22.9 (C-12), 21.6 (C-13), 63.0 (C-14), 12.0 (C-15), 54.0 (N-1), 67.2 (N-2).
Embodiment 9: The compounds of this invention (
9) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
9) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9, (27mg 0.1mmol) is dissolved among the DMF (2ml) 10-alkene-14-chloro Guajol, adds thiomorpholine (50 μ l).70 ℃ of reactions of gained mixture are spent the night.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=1: 1, eluent ethyl acetate) white waxy solid (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-thio-morpholinyl Guajol (
9) 29.3mg, yield 87%.The spectral data of compound is following: MS (ESI)
M/z: 338.2 [M+H]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.00 (1H, brs, H-1), 1.86 (1H, m, H-2a), 1.50 (1H, m, H-2b), 1.86 (1H, m, H-3a), 1.52 (1H, m, H-3b), 1.79 (1H, m, H-4), 2.18 (1H, t,
J=11.4Hz, H-6a), 1.13 (1H, dd,
J=7.5,12.7Hz, H-6b), 1.60 (1H, d,
J=7.6, H-7), 5.71 (1H, s, H-9), 1.39 (1H, m, H-11), 0.86 (3H, d,
J=6.5Hz, H-12), 0.97 (3H, s, H-13), 2.95 (1H,
J=13.3Hz, H-14a), 2.75 (1H,
J=13.3Hz, H-14b), 0.99 (3H, s, H-15), 2.64 (4H, brs, N-1), 2.61 (4H, brs, N-2);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 51.0 (C-1), 27.6 (C-2), 31.4 (C-3), 40.4 (C-4), 87.0 (C-5), 36.9 (C-6), 59.8 (C-17), 103.5 (C-8), 126.7 (C-9), 141.8 (C-10), 31.2 (C-11), 22.9 (C-12), 21.6 (C-13), 63.2 (C-14), 12.0 (C-15), 55.3 (N-1), 28.1 (N-2).
Embodiment 10: The compounds of this invention (
10) preparation
The preparation of midbody: with
Embodiment 1Middle intermediates preparation.
Target compound (
10) preparation:
Will (1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9, (27mg 0.1mmol) is dissolved among the DMF (2ml) 10-alkene-14-chloro Guajol, adds 4-Methoxybenzylamine (100 μ l).70 ℃ of reactions of gained mixture are spent the night.Reaction solution concentrates evaporate to dryness, the gained bullion through PTLC purifying (hexanaphthene: ETHYLE ACETATE=2: 1, eluent ethyl acetate) the colorless oil compound (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-to the amino Guajol of methoxybenzyl (
10) 25.5mg, yield 69%.The spectral data of compound is following: MS (ESI)
M/z: 372.1 [M+H]
+ 1H-NMR (300 MHz, CDCl
3)
δ(ppm): 2.07 (1H, t,
J=9Hz, H-1), 1.90 (1H, m, H-2a), 1.55 (1H, m, H-2b), 1.90 (1H, m, H-3a), 1.55 (1H, m, H-3b), 1.84 (1H, m, H-4), 2.22 (1H, dd,
J=10.7,12.9Hz, H-6a), 1.25 (1H, dd,
J=7.1,12.9Hz, H-6b), 1.65 (1H, dd,
J=3.3,10.6Hz, H-7), 5.78 (1H, s, H-9), 1.50 (1H, m, H-11), 0.90 (3H, d,
J=6.4Hz, H-12), 1.02 (3H, brs, H-13), 3.20 (2H, brs, H-14), 1.04 (3H, brs, H-15), 3.72 (2H, dd,
J=13.0,22.7Hz, H-16), 6.89 (1H, d,
J=8.6 Hz, H-2 ', H-6 '), 7.28 (1H, d,
J=8.6 Hz, H-3 ', H-5 '), 3.82 (3H, s ,-OCH
3);
13C-NMR (75 MHz, CDCl
3)
δ(ppm): 50.7 (C-1), 27.8 (C-2), 31.3 (C-3), 40.5 (C-4), 87.0 (C-5), 36.8 (C-6), 59.6 (C-7), 103.6 (C-8), 124.7 (C-9), 143.0 (C-10), 31.3 (C-11), 22.9 (C-12), 21.6 (C-13), 52.1 (C-14), 12.0 (C-15), 52.7 (C-16), 132.4 (C-1 '), 129.5 (C-2 '; C-6 '), 114.0 (C-3 ', C-5 '), 158.8 (C-4 '), 55.5 (OCH
3).
Embodiment 11: The compounds of this invention anti-influenza A H 1 N 1 virus activity experiment
One, experiment material
1, medicine: Curcumenol verivate sample compound
1 ~ 10
2, diluent 0.1% DMSO-PBS
3, cell: mdck cell
4, virus: A/Hubei/9/2009/ (H1N1)
5, main agents: DMEM (GiBCO), calf serum, foetal calf serum (Sigma), trypsinase etc.
Two, experimental technique
1, cell cultures: in 96 well culture plates, treat that cell grows up to individual layer with cell inoculation;
2, virus multiplication: A/Hubei/9/2009/ (H1N1) (RNA viruses);
3, the mensuration of virus titer
1) inoculating cell in 96 well culture plates is cultured to individual layer and experimentizes;
2) nutrient solution that contains 10% serum in the archeocyte culture plate is shifted out, virus is according to 10
-1, 10
-2, 10
-3, 10
-4,
10
-5, 10
-6, 10
-7With 10
-8Extent of dilution add in the cell plate, behind 35 ℃ of absorption 30min, add cell maintenance medium, set up the normal cell contrast simultaneously, 35 ℃ of cultivations;
3) every day observation of cell the pathology situation, the record result.
4) calculate TCID
50
4, sample cell toxicity test
1) select viral permissive cell MDCK for use, add different concns sample (ug/ml), cultivated 7 days, every day, observation of cell toxicity utilized the R-M formula to calculate median toxic concentration (TD
50) and maximal non-toxic concentration (TD
0), revision test 2 times is confirmed numerical value.
2) sample dissolution method: use DMSO agent dissolves medicine to be made into the mother liquor of concentration, get 1ul during use and use the DMEM substratum to be mixed with the experimental concentration of peak concentration as 100ug/ml, doubling dilution as 10mg/ml; Be followed successively by 100ug/ml; 50ug/m1,25ug/ml, 12.5ug/ml; 6.25ug/ml, 3.125ug/ml.
3) establish the normal cell contrast.
4) experimental result is seen table 1.
5, the antiviral experimental technique of sample
1) virus infection dosage: A/Hubei/9/2009/ (H1N1) TCID
5010
-3.86/ hole;
2) sample is provided with three concentration, with 2
-1TD
50Be peak concentration, be respectively 2
-1TD
50, 2
-2TD
50, 2
-3TD
50
3) 96 orifice plate culturing cells treat that cell grows up to individual layer, add 100ul virus liquid/hole respectively, after absorption half a hour, add the different concns sample respectively, cultivate 24h-96h for 35 ℃, observe CPE.
4) control group: 1. virus+cell; 2. normal cell; 3. Ro 64-0796/002 (Tamiflu) control group.
6, the antiviral experimental result of sample
1) table 1 Curcumenol verivate is to the influence of pathological changes caused by virus effect
2) table 2 Curcumenol verivate is to mdck cell toxicity and external anti-H1N1 influenza virus effect
7, brief summary
Compound of the present invention
4With
8The effect of anti-H1N1 influenza virus is better than Ro 64-0796/002;
1 ~ 3,
5~
7,
9 ~ 10Result of treatment is arranged, but be lower than Ro 64-0796/002 (Tamiflu).
Table 1 Curcumenol verivate is to the influence of pathological changes caused by virus effect
| Infective dose (TCID 50) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | Ro 64-0796/002 | The cell contrast | Virus control |
| 100 | + | ± | + | － | + | + | ± | － | ± | ± | － | － | ++++ |
Annotate :-acellular pathology (good restraining virus function) shown; ± show the cytopathic effect of delaying there be (better inhibited virus function); + show the cytopathy (moderate inhibition virus function) below 1/4; ++ show that 1/4～1/2 cell has pathology (more weak inhibition virus function); The cell of +++show 1/2～3/4 has pathology (weak inhibition virus function); ++ ++ show that the cell more than 3/4 has pathology (unrestraint virus function).
Table 2 Curcumenol verivate is to mdck cell toxicity and external anti-H1N1 influenza virus effect
| Medicine | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | Ro 64-0796/002 |
| TC50 | 299.73 | 690.4 | 578.33 | 966.01 | 347.24 | 475.32 | 286.34 | 827.28 | 224.13 | 667.81 | 1700.86 |
| IC50 | 10.25 | 8.56 | 12.34 | 3.11 | 15.27 | 13.44 | 7.36 | 3.05 | 8.98 | 9.23 | 6.87 |
< 0.001, drug level (Log10) is linear with viral inhibiting rate, and survival rate is three MVs after the mensuration for P
Embodiment 12: The compounds of this invention
4The preparation of tablet
1. write out a prescription:
Compound
4100g
Microcrystalline Cellulose 50g
Pregelatinized Starch 60g
Magnesium Stearate 1.5g
Carboxymethylstach sodium 5g
Prepare 500 altogether
2. preparation technology: raw material, auxiliary material are crossed 100 mesh sieves respectively, subsequent use; Take by weighing raw material and auxiliary material according to recipe quantity; With compound
4, Microcrystalline Cellulose, pregelatinized Starch, mix, it is an amount of to add water, stirs, and processes suitable softwood; Cross 20 mesh sieve system particles; Particle is dried under 60 ° of C conditions; Dry good particle adds Magnesium Stearate and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes; Compressing tablet.
Embodiment 13: The compounds of this invention
4The preparation of aqueous injection
1. write out a prescription:
Compound
42.0g
Tween-80 20ml
Water for injection adds to 1000ml
Prepare 200 altogether
2. preparation technology: with compound
4, tween-80, water for injection dissolving dosing, handle after-filtration, constant volume, smart filter, embedding, sterilization, leak detection, lamp inspection through charcoal absorption, after process the aqueous injection finished product.
Claims (6)
1. the Curcumenol verivate that has the anti-influenza A H 1 N 1 virus of general formula (I):
（Ⅰ）
Wherein, R
1Represent fragrant oxygen base, acyloxy, C
1-6Ring-shaped fat amino (comprise and contain O, the equiatomic heterocycle of S), benzyl amino; R
2Represent OH or OAc.
2. Curcumenol verivate according to claim 1 is characterized in that, described compound is preferred:
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-to aldehyde radical phenoxy Guajol (
1)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8-hydroxyl-14-Guajol acetic ester (
2)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8-hydroxyl-14-Guajol succinate (
3)
(1S, 4S, 5S, 7S, 8R)-5, and 8-epoxy-9,10-alkene-8,14-pockwood ethyl glycol acetate (
4)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-Pyrrolidine base Guajol (
5)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-piperidyl Guajol (
6)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-N-N-METHYL PIPERAZINE base Guajol (
7)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-morpholinyl Guajol (
8)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-thio-morpholinyl Guajol (
9)
(1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-to the amino Guajol of methoxybenzyl (
10)
。
3. preparation method of compound according to claim 1 is characterized in that may further comprise the steps:
(1) Curcumenol exists
mUnder the effect of-CPBA, obtained the compound of 14 double bond epoxidations;
(2) under alkaline condition, through open loop dehydration, formed crucial midbody (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-8,14-pockwood glycol;
(3) hereinto on the basis of mesosome, directly synthetic or with alcoholic extract hydroxyl group be converted into the higher halohydrocarbon of reactivity ratio (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-alkene-14-chloro Guajol obtains target compound.
4. claim 1 or the 2 described compounds application in preparation treatment H 1 N 1 influenza A virus infection property disease medicament.
5. a pharmaceutical composition comprises claim 1 or 2 described compounds and pharmaceutically acceptable excipient.
6. according to any one described compound of claim 1-2 or the described compsn of claim 5, it is characterized in that described compound or compsn and the carrier of pharmaceutically accepting are mixed with the preparation of accepting clinically.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103757685A (en) * | 2014-01-24 | 2014-04-30 | 广东达进电子科技有限公司 | Ceramic circuit board clamp used for electroplating |
| CN111956654A (en) * | 2020-09-25 | 2020-11-20 | 沈阳药科大学 | Application of triazamidine in preparation of furin inhibitor |
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| CN1704417A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Novel curcumenol derivatives |
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2012
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| CN1704417A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Novel curcumenol derivatives |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103757685A (en) * | 2014-01-24 | 2014-04-30 | 广东达进电子科技有限公司 | Ceramic circuit board clamp used for electroplating |
| CN103757685B (en) * | 2014-01-24 | 2016-09-21 | 广东达进电子科技有限公司 | Ceramic circuit board clamp is used in a kind of plating |
| CN111956654A (en) * | 2020-09-25 | 2020-11-20 | 沈阳药科大学 | Application of triazamidine in preparation of furin inhibitor |
| CN111956654B (en) * | 2020-09-25 | 2021-12-28 | 沈阳药科大学 | Application of triazamidine in preparation of furin inhibitor |
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